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Originally published In Press as doi:10.1074/jbc.M207107200 on August 2, 2002

J. Biol. Chem., Vol. 277, Issue 42, 39926-39936, October 18, 2002
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hUNG2 Is the Major Repair Enzyme for Removal of Uracil from U:A Matches, U:G Mismatches, and U in Single-stranded DNA, with hSMUG1 as a Broad Specificity Backup*

Bodil Kavli, Ottar Sundheim, Mansour Akbari, Marit Otterlei, Hilde NilsenDagger , Frank Skorpen, Per Arne Aas, Lars Hagen, Hans E. Krokan, and Geir Slupphaug§

From the Institute of Cancer Research and Molecular Biology, Norwegian University of Science and Technology, N-7489 Trondheim, Norway

hUNG2 and hSMUG1 are the only known glycosylases that may remove uracil from both double- and single-stranded DNA in nuclear chromatin, but their relative contribution to base excision repair remains elusive. The present study demonstrates that both enzymes are strongly stimulated by physiological concentrations of Mg2+, at which the activity of hUNG2 is 2-3 orders of magnitude higher than of hSMUG1. Moreover, Mg2+ increases the preference of hUNG2 toward uracil in ssDNA nearly 40-fold. APE1 has a strong stimulatory effect on hSMUG1 against dsU, apparently because of enhanced dissociation of hSMUG1 from AP sites in dsDNA. hSMUG1 also has a broader substrate specificity than hUNG2, including 5-hydroxymethyluracil and 3,N4-ethenocytosine. hUNG2 is excluded from, whereas hSMUG1 accumulates in, nucleoli in living cells. In contrast, only hUNG2 accumulates in replication foci in the S-phase. hUNG2 in nuclear extracts initiates base excision repair of plasmids containing either U:A and U:G in vitro. Moreover, an additional but delayed repair of the U:G plasmid is observed that is not inhibited by neutralizing antibodies against hUNG2 or hSMUG1. We propose a model in which hUNG2 is responsible for both prereplicative removal of deaminated cytosine and postreplicative removal of misincorporated uracil at the replication fork. We also provide evidence that hUNG2 is the major enzyme for removal of deaminated cytosine outside of replication foci, with hSMUG1 acting as a broad specificity backup.

* This work was sponsored by the Norwegian Cancer Society; the Research Council of Norway; the Cancer Fund at St. Olavs Hospital, Trondheim, Norway; and the Svanhild and Arne Must Fund for Medical Research.The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Dagger Present address: Cancer Research UK London Research Inst., Clare Hall Laboratories, South Mimms, Hertfordshire EN6 3LD, United Kingdom.

§ To whom correspondence should be addressed. Tel.: 47-73598693; Fax: 47-73598801; E-mail: geir.slupphaug@medisin.ntnu.no.

Copyright © 2002 by The American Society for Biochemistry and Molecular Biology, Inc.


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